Elevated low density lipoproteins (LDL) cholesterol and decreased high density lipoproteins (HDL) cholesterol are two defined risk factors associated with increased coronary artery disease (CAD). Conversely, low levels of LDL cholesterol and high levels of HDL cholesterol are associated with a decreased risk of CAD. Furthermore, pharmacologic intervention with the lipid lowering agents nicotinic acid and cholestyramine demonstrate that LDL cholesterol lowering is associated with a decreased risk of CAD. These data suggest that modulation of apolipoprotein concentration levels may result in a decrease of CAD. The projects summarized here are concerned with treatment or prevention of CAD by developing new strategies for lowering LDL cholesterol and to better understand HDL cholesterol physiology so that new approaches can be developed to increase HDL cholesterol. With respect to lowering LDL cholesterol, a means of decreasing the synthesis of the major protein associated with the LDL particle transport, apoB, is being developed using the agent vanadate. Vanadate appears to decrease apoB synthesis by decreasing apoB mRNA levels. Other currently used agents decrease LDL cholesterol through other mechanisms, so this approach could add another treatment modality. With respect to increasing HDL cholesterol, our studies evaluated the human sources of the two major proteins in HDL, apoA-l and apoA-ll, and found that the liver made both apoproteins, whereas the small intestine only made apoA-I. Since the apparent best HDL predictor of protection from CAD appears to be the quantity of HDL particles containing only apoA-I, the suggestion is that the small intestine may be the best target for intervention to selectively increase apoA-l only HDL particles.